Parkinson's Disease (PD) is a progressive disorder of the central nervous system affecting over 1.5 million people in the United States. Parkinson's disease is caused by the degeneration of the pigmented neurons in the substantia nigra of the brain, resulting in decreased dopamine availability to the striatum. Clinically, the disease is characterized by an increase in spontaneous movements, gait difficulty, postural instability, rigidity and tremor. Presently, there is no known cause or cure of PD.
The conventional method of treating Parkinson's disease involves the administration of a dopamine agonist, such as levodopa (L-DOPA), administered either alone or in combination with a peripheral dopa decarboxylase inhibitor, such as carbidopa, to a patient suffering from this disorder to restore the nigro-neostriatal hypofunction by increasing the post-synaptic dopamine receptor stimulation. After about 5 years of treatment, however, the majority of PD patients experience a “wearing-off” of drug effect, and often exhibit abnormal motor side effects (e.g., dyskinesias and dystonias) in response to the L-DOPA. It is believed that the development of L-DOPA induced-dyskinesias result from severe nigrostriatal denervation in combination with chronic L-DOPA treatment for a period of time of months to years. These problems limit the long-term benefit that can be achieved with L-DOPA. Once the dyskinesias manifest themselves, the therapeutic options that can be offered to the patient are reduced.
Research in recent years indicates that, depending on neuronal environments, nitric oxide (NO) can initiate and mediate either neuroprotection or neurotoxicity. NO-related agents span the range from prodrugs that elevate NO levels, to scavengers of NO, and inhibitors of endogenous NO synthesis. The term “NO-donor” is used almost universally for NO-related drugs manifesting biological activity that mimics endogenous NO. NO-donors do not fit the traditional receptor-targeted drug design paradigm. NO donors are by definition prodrugs. As prodrugs, NO donors are not readily amenable to in vitro high throughput drug screening. Currently known NO-donors cover a wide range of chemical substances and classes. As such, NO-donors are not expected to manifest identical physiological actions.